5433
J. Org. Chem. 1990,55, 5433-5434
Asymmetric Total Synthesis of (-)-Secodaphniphylline' Jeffrey A. Stafford and Clayton H. Heathcock* Department of Chemistry, University of California, Berkeley, California 94720 Received August 10, 1990
Summary: An asymmetric total synthesis of (-)-secodaphniphylline ( 5 ) is described. The desired absolute stereochemistry is established in two stereoselective transformations-an asymmetric Michael reaction of amide 8 and an asymmetric reduction of ketone 14. The Daphniphyllum alkaloids are a family of squalene-derived natural products having diverse and complex structures., Most members of the group have truncated structures, in which only 22 skeletal carbons of the biogenetic progeniter remain. Examples are methyl homosecodaphniphyllate ( l ) ,methyl homodaphniphyllate (2), daphnilactone A (3),3 and yuzurimine (4). In the known Daphniphyllum alkaloids that retain the entire complement of squalene carbons the first eight carbons of squalene molecule are fashioned into a bicyclic array, as exemplified in the structures of the Cs0Daphniphyllum alkaloids secodaphniphylline (5) and daphniphylline (6). We have reported total syntheses of racemic versions of alkaloids 1-3.134 However, apart from a synthesis of (f)-proto-daphniphylline (7), the conjectured biosynthetic pentacyclic parent of the entire family,5 none of the C30 Daphniphyllum alkaloids have been fabricated. In this paper we report a total synthesis of (-)-secodaphniphylline ( 5 ) . The convergent route employed uses an asymmetric Michael addition to acquire an enantiomeric excess in the pentacyclic nitrogen-containing moiety and an asymmetric carbonyl reduction for the same purpose in preparation of the 2,8-dioxabicyclo[3.2.l]octane unit. The enantiomeric purity available in the two synthetic subunits (90-92% ee) is greatly magnified in the coupling reaction, and the synthetic (-)-secodaphniphylline is calculated to be approximately 99.6% ee. The synthesis of (-)-l is summarized in Scheme I. Amide 8 was prepared from 5-(benzy1oxy)pentanoyl under Schotchloride and (S,S)-2,5-dimethylpyrr~lidine~ ten-Baumann conditions. A tetrahydrofuran (THF) solution of the lithium enolate of 8 was treated with unsaturated ester 9 and then with a solution of homogeranyl iodide in hexamethylphosphoric amide (HMPA) at -78 "C. The major product, homogeneous under several chromatographic conditions, was isolated in 64% yield. For reasons to be explained shortly, we believe that this product is actually a mixture of two diastereomers in a ratio of approximately 92:8, with the major isomer being 10 and the minor one being enantiomeric at each of the three stereocenters created in the Michael and alkylation reactions. The Michael addition, then, occurs with an enan'
(1) Part 8 in a series of papers on the Daphniphyllum alkaloids. For part 7, see: Ruggeri, R.; Heathcock, C. H. J. Org. Chem. 1990,55, 3714. (2) (a) Yamamura, S.; Hirata, Y. In The Alkaloids; Manske, R. H. F., Ed.; Academic: New York, 1975; Vol. 15, p 41. (b) Yamamura, S.; Hirata, Int. Rev. Sci., Org. Chem., Ser. 2 1976,9, 161. (c) Yamamura, S. In Y. The Alkaloids; Brossi, A., Ed.; Academic: New York, 1986; Vol. 29, p 265. (3) Daphnilactone A actually has 23 carbons, the additional one presumably arising from a formaldehyde equivalent: (a) Yamamura, s.; Terada, Y. Chem. Lett. 1976,1381. (b) Ruggeri, R. B.; Heathcock, C. H. Pure Appl. Chem. 1989, 61, 289. (4) (a) Heathcock, C. H.; Davidsen, S. K.; Mills, S.;Sanner, M. A. J . Am. Chem. SOC.1986, 108, 5650. (b) Ruggeri, R. B.; Hansen, M. M.; Heathcock, C. H. Ibid. 1988,110,8734. (c) Ruggeri, R. B.; McClure, K. F.; Heathcock, C. H. Ibid. 1989, 111, 1530. (5) Piettre, S.; Heathcock, S. Science (Washington,D.C.)1990,248, 1532. (6) (a) Whitesell, J. K.; Felman, S. W. J. Org. Chem. 1977, 42, 1663. (b) Schlessinger, R. H.; Iwanowicz, E. J. Tetrahedron Lett. 1987,28,2083.
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tioselectivity of 84% ee, in accord with expectations on the basis of a similar reaction reported by Yamaguchi.' Reduction of 10 proceeded without incident, providing hydroxy amide 11 (73%), which was converted into lactone 12 by treatment with 5 N KOH in ethylene glycol at 165 "C for 50 h, followed by acidification (92%). The conversion of scalemica 12 into (-)-methyl homosecodaphniphyllate (1) exactly parallelled the previously reported synthesis of the racemic alkaloid.3b The material so obtained had mp 77-80 "C and [aID= -82" (c = 1.12, CHC13), corresponding to 835% ee. Recrystallization from hexane gave material with mp 98-99 "C and [a]D= -88" (c = 0.31, CHCl,), corresponding to 90% eea9 The characteristic Daphniphyllum 2,8-dioxabicyclo[3.2.l]octane unit was prepared starting with ketal acid 131° as shown in Scheme 11. Treatment of the derived N-methoxy-N-methylamide [ ( l ) carbonyldiimidazole, CH,Cl,, 10 min; (2) N,O-dimethylhydroxylaminehydrochloride]" with 1-butynyllithium in T H F gave ketone 14 (86%). Compound 14 was reduced with the LiA1H4/ Darvon alcohol complex12 at -80 OC in ether to obtain (7) Yamaguchi, M.; Hasabe, K.; Tanaka, S.; Minami, T. Tetrahedron Lett. 1986, 27, 959. (8) The term scalemic has been suggested by James Brewster (Purdue University) to describe an unequal mixture of enantiomers. According to Brewster's suggestion, scalemic and racemic are macroscopic analogues of chiral and achiral, adjectives that should be reserved for single objects such as molecules. (9) Natural (-)-methyl homosecodaphniphyllate has mp 102.5-3 "C (ref 16). Although the optical rotation is not reported in the literature, we have found [a],,= -97' (c = 0.79, CHCl,) with a sample provided by Prof. Yamamura. (10) Bruice, T. C.; Piszkiewicz, D. J . Am. Chem. SOC. 1967,89, 3568. (11) Nahm, S.; Weinreb, S. Tetrahedron Lett. 1981,22, 3815.
0 1990 American Chemical Society
5434
J. Org. Chem., Vol. 55, No. 20, 1990
Communications Scheme I
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in 95% yield.15 Oxidation of the 17/18 mixture with ruthenium tetroxide and sodium periodate16 gave the corresponding mixture of acids, which were esterified with diazomethane. The resulting esters are easily separated by chromatography on silica gel. The major isomer was saponified with alcoholic KOH to provide ketal acid 19, mp 105-7 "C, in 31% yield, based on the mixture of hydroxy ketals. The enantiomeric purity of 19 was found to be 92% ee by application of Mosher's method13 to the corresDonding Drimarv alcohol. Treatment of 19 with oxalyl-chloridk ^furnished acyl chloride 20 (100%). Mixed Claisen coupling was accomplished by treating the lithium enolate of (-)-1 in T H F with 20 in T H F at -78 "C. The resulting mixture of diastereomeric @-ketoesters was treated with sodium cyanide in dimethyl sulfoxide at 150 "C to produce in 43% yield (-)-secodaphniphylline, mp 124-5 "C, [aID= -50 f 1" (c = 0.35, CHC1,) (lit." mp 129-30 "C, [a],,= -51 f 0.5" (c = 1.06, CHC13)).18J9 The calculated enantiomeric purity of the synthetic secodaphniphylline is 99.6%.20,21
Scheme I1
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alcohol 15 (%TO),shown by conversion into the ester of (R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid13to be 92% ee. Treatment of (-1-15 with potassium 3aminopropanamide (KAPA)14 in 1,3-propanediamine at -15 "C for 45 min afforded alcohol 16 (87%). Treatment of 16 with mercuric sulfate and dilute sulfuric acid in T H F provided bicyclic hydroxy ketals 17 and 18 as a 5:l mixture (12) (a) Yamaguchi, S.; Mosher, H. S. J . Org. Chem. 1973, 38, 1870. (b) Cohen, N.; Lopresti, R. J.; Neukom, C.; Saucy, G.Ibid. 1980,45,582. (13) Dale, J. A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34, 2543. (14) (a) Brown, C. A.; Yamashita, A. J. Am. Chem. SOC. 1975,97,891. (b) Midland, M. M.; Halterman, R. L.; Brown, C. A.;Yamaichi, A. Tetrahedron Lett. 1981,22, 4171.
Acknowledgment. This work was supported by a grant from the National Science Foundation (CHE-84-18437) and by fellowships granted to J.A.S. by Smith, Kline, and French Research Laboratories and the United States Public Health Service. We thank Professor S. Yamamura for a sample of natural secodaphniphylline. Supplementary Material Available: Spectral data for all of the new compounds and intermediates reported; IR and 500MHz 'H NMR spectra of synthetic and natural secodaphniphylline; expansion of the 6 2.4-4.8 region in the 500-MHz 'H NMR spectra of synthetic secodaphniphyllineand a 2:l mixture of the racemic alkaloid and its diastereomer (12 pages). Ordering information is given on any current masthead page. (15) The racemic counterparts of 17 and 18 have been prepared previously: Irikawa, H.; Ishikura, T.; Okumura, Y. Boll. Chem. SOC.,Jpn. 1977,50, 2811. (16) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J . Org. Chem. 1981,46, 3936. (17) Toda, M.; Hirata, Y.;Yamamura, S. Tetrahedron Lett. 1972,28, 1477. We observed mp 119-121 "C (sealed capillary) for an authentic sample of (-)-5 provided by Prof. Yamamura. (18) The uncertainty in [ a ] is due to the uncertainty in weighing precision. (19) Similar coupling of ( f ) - 1 and (f)-20 gave in 44% yield a 21 mixture of (f)-secodaphniphylline and the diastereomer resulting from coupling of the major enantiomer of 1 with the minor enantiomer of 20 (and vice versa). (20) The calculation is based on the enantiomeric purities of the 1 and 20 (95:5 and 96:4, respectively). I t has been pointed out previously that coupling of two enantiomerically enriched units can lead to a major diastereomer of much higher enantiomeric purity than either reactant. (a) Kogure, T.; Eliel, E. L. J . Org. Chem. 1984,49, 576. (b) Midland, M. M.; Gabriel, J. Ibid. 1985, 50, 1144. (21) Although the calculated ratio of (-)-5 and its diastereomer is 96:4, we are unable to detect the diastereomer in the 5@-MHz 'H NMR spectrum of the reaction product (see the supplementary material for an expansion of a diagnostic region of the spectrum of synthetic (-)-5).
